title: Evolution of the hemagglutinin protein of the new pandemic H1N1 influenza virus: maintaining optimal receptor binding by compensatory substitutions.
abstract: Pandemic influenza A H1N1 (pH1N1) virus emerged in 2009. In the subsequent 4 years, it acquired several genetic changes in its hemagglutinin (HA). Mutations may be expected while virus is adapting to the human host or upon evasion from adaptive immune responses. However, pH1N1 has not displayed any major antigenic changes so far. We examined the effect of the amino acid substitutions found to be most frequently occurring in the pH1N1 HA protein before 1 April 2012 on the receptor-binding properties of the virus by using recombinant soluble HA trimers. Two changes (S186P and S188T) were shown to increase the receptor-binding avidity of HA, whereas two others (A137T and A200T) decreased binding avidity. Construction of an HA protein tree revealed the worldwide emergence of several HA variants during the past few influenza seasons. Strikingly, two major variants harbor combinations of substitutions (S186P/A137T and S188T/A200T, respectively) with opposite individual effects on binding. Stepwise reconstruction of the HA proteins of these variants demonstrated that the mutations that increase receptor-binding avidity are compensated for by the acquisition of subsequent mutations. The combination of these substitutions restored the receptor-binding properties (avidity and specificity) of these HA variants to those of the parental virus. The results strongly suggest that the HA of pH1N1 was already optimally adapted to the human host upon its emergence in April 2009. Moreover, these results are in agreement with a recent model for antigenic drift, in which influenza A virus mutants with high and low receptor-binding avidity alternate.
authors.affiliation: Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands.
authors.forename: Robert P
authors.initials: RP
authors.lastname: de Vries
authors.forename: Erik
authors.initials: E
authors.lastname: de Vries
authors.forename: Carles
authors.initials: C
authors.lastname: Martínez-Romero
authors.forename: Ryan
authors.initials: R
authors.lastname: McBride
authors.forename: Frank J
authors.initials: FJ
authors.lastname: van Kuppeveld
authors.forename: Peter J M
authors.initials: PJ
authors.lastname: Rottier
authors.forename: Adolfo
authors.initials: A
authors.lastname: García-Sastre
authors.forename: James C
authors.initials: JC
authors.lastname: Paulson
authors.forename: Cornelis A M
authors.initials: CA
authors.lastname: de Haan
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019143:Evolution, Molecular; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D007251:Influenza, Human / Q000453:epidemiology / Q000378:metabolism / Q000821:virology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009975:Orthomyxoviridae / Q000737:chemistry / Q000145:classification / Q000235:genetics; D058873:Pandemics; D010802:Phylogeny; D011991:Receptors, Virus / Q000378:metabolism*
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D011991:Receptors, Virus